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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE KARNATAKA ANNEXURE – II PROFORMA OF REGISTRATION OF SUBJECT OF DISSERTATION 1. NAME OF THE CANDIDATE AND ADDRESS 2. NAME OF THE INSTITUTION VISVESWARAPURA INSTITUTE OF PHARMACEUTICAL SCIENCES BANGALORE – 70 3. COURSE OF THE STUDY AND SUBJECT MASTER OF PHARMACY IN PHARMACEUTICS 4. DATE OF ADMISSION OF THE COURSE 27/06/2008 5. TITLE OF THE TOPIC VIJAY V. KATHIRIYA #50, 1st FLOOR, 4th MAIN, 5th CROSS, NEAR BALAJI KALYAN MANTAPA, BSK 3rd STAGE, BANGALORE-85 FORMULATION AND EVALUATION OF SUSTAINED RELEASE MICROSPHERES OF ANTIDIABETIC DRUG 6. BRIEF RESUME OF THE PROJECT STUDY 6.1 NEED FOR THE STUDY: The purpose of investigation in this research work is to formulate and evaluate sustained release microsphere of antidiabetic drug for maintenance of glucose levels in the body for 8 to 12 hours. Background of the invention microparticles, microspheres, and microcapsules, referred to herein collectively as "microparticles", are solid or semi-solid particles having a diameter of less than one millimeter, more preferably less than 100 microns, which can be formed of a variety of materials, including synthetic polymers, proteins, and polysaccharides. Microparticles have been used in many different applications, primarily separations, diagnostics, and drug delivery. The categories of physiologically active agents which can be used in the present invention include, but are not limited to, antibiotics, hematopoietics, anti-infective agents, antidementia agents, antiviral agents, antitumor agents, antipyretics, analgesics, anti-inflammatory agents, antiulcer agents, antiallergic agents, antidepressants, psychotropic agents, cardiotonics, antiarrythmic agents, vasodilators, antihypertensive agents such as hypotensive diuretics, antidiabetic agents, anticoagulants, cholesterol lowering agents, therapeutic agents for osteoporosis, hormones, vaccines. 1 The primary benefit of a sustained release dosage form, compared to a conventional dosage form, is the uniform drug plasma concentration and therefore uniform therapeutic effect. Over the past two decades, sustained release dosage forms have made significant progress in terms of clinical efficacy and patient compliance. Matrix devices, due to their chemical inertness, drug embedding ability and drug release character, have gained steady popularity for sustaining the release of a drug.2 In the controlled drug delivery area, molecules are encapsulated within microparticles or incorporated into a monolithic matrix, for subsequent release. A number of different techniques are routinely used to make these microparticles from synthetic polymers, natural polymers, proteins and polysaccharides, including phase separation, solvent evaporation, emulsification, and spray drying. Generally the polymers form the supporting structure of these microspheres, and the drug of interest is incorporated into the polymer structure. Exemplary polymers used for the formation of microspheres include homopolymers and copolymers of lactic acid and glycolic acid (PLGA) as described in U. S.1 2 6.2 REVIEW OF LITERATURE: 1. Sustained release microspheres of chlorpromazine were prepared from Eudragit® RS 100 by an emulsion-solvent evaporation method using a sixbaffled vessel. The morphology of microspheres was characterized by scanning electron microscopy (SEM). In the presence of aluminium tristearate (5%), microspheres were spherical in shape and uniform. The release of chlorpromazine from microspheres was pH-independent. With increasing amount of aluminium tristearate and increasing ratio of Eudragit® RS 100/drug from 1:1 to 9:1, the particle size of chlorpromazine microspheres was reduced and the release rate decreased. The microspheres prepared with the polymer/drug ratio of 9:l produced a 12-h sustained release pattern.3 2. Meclofenamic acid (MFA) sustained-release microspheres were prepared by the solvent evaporation method using cellulose propionate (CP) polymer and acetone as the polymer solvent. Polyethylene glycol (PEG) was used as a channeling agent to improve the release properties of MFA at 1:2:1 drug to polymer to PEG ratio. The microspheres prepared at three different speeds (600, 800 and 1000 rpm) were characterized and release profiles were carried out in phosphate buffer, pH 8.0 at 37°C.The release rate of MFA from these microspheres was not affected by the molecular weight of CP polymer. PEG 2000 was found to have a more enhancing effect on the rate of the release than PEG 4000.4 3. Metoclopramide was encapsulated with poly (D, L-lactide co glycolide) copolymers of different molecular weights using the emulsification/solvent evaporation technique. The effect of the polymers' molecular weights as well as the polymer-to-drug ratios on the microsphere preparation was investigated. The release rate of the drug was studied for 96h in a phosphate buffer of pH 7.4. Data revealed that a higher yield was obtained with polymers of lower molecular weights. A lower yield was also obtained with increasing the drug-to-polymer ratios. The release of the drug mainly followed zero order kinetics. The release rate was a function of both the polymers' molecular weights and the drug-to-polymer ratios.5 4. Ofloxacin microspheres were formulated using polyglycolic acid-co-dllactic acid (PGLA) by the emulsion solvent evaporation technique. Ofloxacin release from the microspheres was biphasic with an initial burst release followed by a slow release phase. An optimum slowing down of release was observed when the phase volume was 29%. Above and below this phase volume, release of ofloxacin was higher. The study indicates that various rates of ofloxacin release are possible by varying formulation conditions. This should provide a means for formulating sustained release microspheres of antibiotics for the treatment of biofilm infections associated with the bone.6 3 5. Ethylcellulose is used as a retardant to prepare the sustained release of potassium chloride microspheres by drying in a liquid process. The effect of sustained release of potassium from ethylcellulose microspheres was evaluated by the in vitro dissolution test, and was compared to a commercial product (Slow-K). Satisfactory results could be obtained considering size distribution and shapes of microspheres by incorporating aluminum stearate. Satisfactory results could be obtained considering size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84–93 and 36%, respectively.7 6. Ketoprofen microspheres (MS) were prepared by the dry-in-oil method using ethylcellulose (EC) as a matrix polymer. Further, the microspheres modified by addition of polyethylene glycol (PEG) and hydroxypropyl cellulose (HPC), called MS-P and MS-H, respectively, were prepared. The in vitro release was examined in pH 6.8, at 37°C and 60 rpm. Chitosancoated ketoprofen microparticles (Chi-MP) were prepared by the precipitation technique and evaluated for adhesion. The microspheres with moderate drug content, prepared by addition of modest amount of PEG, exhibited better gradual drug release. Chi-MP showed agood mucoadhesion. Chi-MP tended to show the higher and steadier plasma levels than MS.8 7. Methacrylate microparticles were prepared by Spray-drying for the delivery of ascorbic acid via the oral route. As polymers different acrylic compounds were considered, namely Eudragit® RL, L and RS. Microspheres were first characterized by size and morphology by scanning electron microscopy, then in vitro release kinetics by mean of dialysis method were studied. These microspheres showed a good morphology and size distribution that permit to propose them as candidate for the delivery of vitamin C.9 8. Microparticles containing diltizem hydrochloride were prepared by the spray-drying technique using acrylatemethacrylatecopolymers, Eudragit RS and Eudragit RL, as coating materials. Spray-drying using dichloromethane as the solvent resulted in microspheres whereas using toluene gave microcapsules with the drug coated by the polymer. The particle size distribution for both microspheres and microcapsules was narrow. The results indicate that spray-drying is a method that can be used to prepare microparticles from the Eudragit acrylic resins RLand RS with a narrow particle size distribution. Drug release rate can be controlled by choice of polymer type and production conditions during spray-drying.10 4 9. Sustained release (SR) particles for pulmonary drug delivery using terbutalin sulphate were prepared using spray dryer. Sustained release of the model drug, from the microspheres was proportional to drug loading and phospholipids content. Microspheres with a 33% drug loading exhibited sustained release of 32.7% over 180 min in phosphate buffer. No significant burst release was observed which suggested that nanoparticles were coated effectively during spray-drying. The sustained release microspheres were formulated as a carrier-free dry powder for inhalation.11 10. Ketoprofen microspheres were prepared by a spray-drying technique using cellulose acetate butyrate (CAB) and hydroypropylmethylcellulose phthalate (HPMCP), in different weight ratios. Spray-dried microparticles were characterized in terms of shape, size, and production yield and encapsulation efficiency. Tablets were prepared by direct compression of the microparticles mixed with maltose and, in some cases, hydroypropylmethylcellulose (HPMC). In-vitro release studies were performed both at acidic and neutral pHs. The microparticles give a rapid or prolonged drug release.12 6.3 OBJECTIVES OF THE STUDY: 7. The objective of this study was to prepare sustained release microspheres using various polymers. To evaluate the particle size, drug entrapment efficiency, drug content, In-vitro release study. In order to elucidate release kinetics it is necessary to fit drug release data into a suitable model. The commonly adopted models for understanding the release of drugs from matrices are zero-order equation, first-order equation, Higuchi equation and Korsmeyer-Peppas simple exponential equationmodels. These simple exponential equation models have been used to elucidate the mode of release. MATERIALS AND METHODS Drug: A model antidiabetic drug. Method: Spray drying technique. 5 7.1 SOURCE OF DATA Journals, Internet, Text books, Web resources and E journals (European Journal of Pharmaceutics and Biopharmaceutics, Indian journal of pharmaceutical science,) and experimental works which includes formulation evaluation and stability studies. 7.2 METHOD OF COLLECTION OF DATA The data related to physiochemical details of the drug will be collected from drug information center, various standard books, journals & other sources like research literature data bases such as science direct etc and laboratory experiments. 7.3 DOES THE STUDY REQUIRE ANY INVESTIGATIONS OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS? IF SO PLEASE DESCRIBE BRIEFLY -No7.4 ETHICAL CLEARANCE: -NA7.5 PLACE OF STUDY: Visveswarapura Institute Of Pharmaceutical Sciences, Bangalore-70. 8. LIST OF REFERENCES: 1. Scott TL, Brown LR, Riske FJ, Blizzard CD, Rashba-Step J. Sustained release microspheres. 09/420,361 18.10.1999 US 2. Basak SC, Kumar KS, Ramlingam M. Design and release characteristics of sustained release tablet containing metformin HCl. Rev Bras Cienc Farm 2008; 44(3). 3. Gao ZG, Oh KH, Kim CK. Preparation and characterization of sustainedrelease microspheres of chlorpromazine. J Microencapsul 1998; 15(1): 7583. 4. Khidr SH, Niazy EM, El-Sayed YM. Development and In-vitro evaluation of sustained-release meclofenamic acid microspheres. J Microencapsul 1998; 15(2): 153-63. 6 5. Elkheshen SA, Radwan MA. Sustained release microspheres of metoclopramide using poly (D,L-lactide-co-glycolide) copolymers. J Microencapsul 2000; 17(4): 425-35. 6. Habib M. Preparation and characterization of ofloxacin microspheres for the eradication of bone associated bacterial biofilm. J Microencapsul 1990; 16(1): 27-37. 7. Wu PC, Huang YB, Chang JI, Tsai MJ, Tsai YH. Preparation and evaluation of sustained release microspheres of potassium chloride prepared with ethylcellulose. Int J Pharm 2003; 260(1): 115-21. 8. Yamada T, Onishi H, Machida Y. In-vitro and In-vivo evaluation of sustained release chitosan-coated ketoprofen microparticles. Yakugaku Zasshi 2001; 121(3): 239-45. 9. Esposito E, Cervellati F, Menegatti E, Nastruzzi C, Cortesi R. Spray dried eudragit microparticles as encapsulation devicesfor vitamin C. Int J Pharm 2002; 242: 329-43. 10. Kristmundsdottir T, Gudmundsson OS, Ingvarsdottir K. Release of diltiazem from eudragit microparticles prepared by spray-drying. Int J Pharm 1996; 137: 159-65. 11. Cook RO, Pannu RK, Kellaway IW. Novel sustained release microspheres for pulmonary drug delivery. J cont release 2005; 104(1): 79-90. 12. Moretti MDL, Gavini E, Juliano C, Pirisino G, Giunchedi P. Spray-dried microspheres containing ketoprofen formulated into capsules and tablets. J Microencapsul 2001; 18(1): 111-21. 7 9. 10. 11. 11.1 SIGNATURE OF THE CANDIDATE REG NO. REMARKS OF THE GUIDE NAME AND DESIGNATION OF GUIDE DR. PRAKASH RAO. B Professor and HOD Department of pharmaceutics, V.I.P.S., Bangalore-560070 SIGNATURE 11.2 HEAD OF THE DEPARTMENT DR. PRAKASH RAO. B Professor Department of pharmaceutics, V.I.P.S., Bangalore-560070 SIGNATURE 12. REMARKS OF THE PRINCIPAL SIGNATURE WITH SEAL 8